Stress, reward and homeostasis. Role of the brain´s neural networks and their interplay with peripheral tissues in type 2 diabetes development

PurposeTo explore whether an altered ‘glucostat’ function of the brain is instrumental in the development (and reversal) of type 2 diabetes (T2D).

To elucidate the role of neural networks including hypothalamus, dopaminergic/serotonergic systems and neuroendocrine pathways communicating with peripheral organs.Research questions on T2D development:Role of the brain and specific neurocircuits, in particular monoaminergic?Increased activity in glucose-raising neuroendocrine pathways?Molecular mechanisms and targets: which neurotransmitters and receptors are involved and can point to novel treatments?

MethodsNormal, overweight, prediabetic individuals, respectively, and patients with T2D are investigated during normo-, hyper- and hypoglycemic clamps:Neuroimaging using neurtransmitter-PET and functional MRIGlucose-raising hormonal responses Autonomic nerve activity Metabolic responses (glucose and lipid handling in vivo)In addition, rats and zebrafish will undergo diet and pharmacological interventions.

Behavioral, metabolic, neurochemical and neuroendocrine profiling will provide mechanisms, causality and molecular drug targets. Later pilot interventions in humans will use approved medicines, targeting dopaminergic and other brain neurocircuits. This will validate exploratory findings. ImpactThis multidisciplinary project will define brain-mediated ‘glycemic resetting’ in T2D development.

It will provide new mechanisms and tools for personalized prevention and treatment of T2D.